EP1992361B1 - Remedy or preventive for digestive ulcer - Google Patents

Remedy or preventive for digestive ulcer Download PDF

Info

Publication number
EP1992361B1
EP1992361B1 EP07714807A EP07714807A EP1992361B1 EP 1992361 B1 EP1992361 B1 EP 1992361B1 EP 07714807 A EP07714807 A EP 07714807A EP 07714807 A EP07714807 A EP 07714807A EP 1992361 B1 EP1992361 B1 EP 1992361B1
Authority
EP
European Patent Office
Prior art keywords
nmr
branched
linear
alkyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP07714807A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP1992361A4 (en
EP1992361A1 (en
Inventor
Masakatsu Kawakami
Yoshihiro Keto
Ken Ikeda
Mari Fukuda
Junji Sato
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Astellas Pharma Inc
Original Assignee
Astellas Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astellas Pharma Inc filed Critical Astellas Pharma Inc
Priority to PL07714807T priority Critical patent/PL1992361T3/pl
Publication of EP1992361A1 publication Critical patent/EP1992361A1/en
Publication of EP1992361A4 publication Critical patent/EP1992361A4/en
Application granted granted Critical
Publication of EP1992361B1 publication Critical patent/EP1992361B1/en
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a pharmaceutical composition for use in a method of treatment or prevention of digestive ulcer, comprising a non-purine-structure xanthine oxidase inhibitor of formula (I) as an active ingredient, in particular to a pharmaceutical composition for treatment or prevention for ulcer that are formed in digestive tracts by the attack thereto such as gastric acid, pepsin, stress, Helicobacter pylori , NSAID (non-steroidal antiinflammatory drug), etc.
  • a pharmaceutical composition for use in a method of treatment or prevention of digestive ulcer comprising a non-purine-structure xanthine oxidase inhibitor of formula (I) as an active ingredient, in particular to a pharmaceutical composition for treatment or prevention for ulcer that are formed in digestive tracts by the attack thereto such as gastric acid, pepsin, stress, Helicobacter pylori , NSAID (non-steroidal antiinflammatory drug), etc.
  • NSAID non-steroidal antiinflammatory drug
  • the digestive ulcer indicates an ulcer in which the partial defect of the epithelial tissue in the mucosal layer of a digestive tract has reached the depth.
  • the basic consideration for the reasons for the pathogenesis is a balance theory that the balance between the aggressive factor such as gastric acid, pepsin, stress, Helicobacter pylori, NSAID, etc. and the mucosal membrane protecting factors for digestive tracts, i.e., the equilibrium of the function of mucus/mucosa barrier and blood flow/microcirculation, growth factor and prostaglandin, may be lost to form an ulcer ( Chiryogaku, 2005; 39(5): 8-10 ; Can. J. Gastroenterol., 1999, Nov.; 13(9): 753-9 ).
  • Allopurinol is known as an agent for treating gout and hyperuricemia, and this compound inhibits xanthine oxidase to thereby exhibit the action of lowering the serum uric acid level ( Am. J. Manag. Care., 2005 Nov; 11(15 Suppl.): S451-8 ).
  • the compound has a nucleic acid-derived structure (purine-like structure), and many side effects have been reported, which are considered to be based on the inhibition of the nucleic acid metabolism ( Am. J. Med. 1984 Jan; 76(1):.47-56 ; Isr. Med. Assoc. J., 2005 Oct; 7(10): 656-60 ; Biol. Pharm.
  • phenylazole-carboxylic acid derivatives such as 2-phenylthiazole derivatives (Patent References 1 to 3), 3-phenylisothiazole derivatives (Patent Reference 4 and Patent Reference 5), phenylpyrazole derivatives (Patent Reference 6, Patent Reference 7 and Patent Reference 8), 2-phenyloxazole derivatives (Patent Reference 9), 2-phenylimidazole derivatives (Patent Reference 9).
  • phenylazole-carboxylic acid derivatives such as 2-phenylthiazole derivatives (Patent References 1 to 3), 3-phenylisothiazole derivatives (Patent Reference 4 and Patent Reference 5), phenylpyrazole derivatives (Patent Reference 6, Patent Reference 7 and Patent Reference 8), 2-phenyloxazole derivatives (Patent Reference 9), 2-phenylimidazole derivatives (Patent Reference 9).
  • Non-Patent References 1 to 3 Some reports say that allopurinol is effective for models with upper and lower digestive ulcers at an extremely high-level dose (Non-Patent References 1 to 3).
  • Non-Patent Reference 1 has a description discussing that allopurinol has a xanthine oxidase-inhibiting effect and expresses the effect by inhibiting the production of free radicals.
  • Non-Patent Reference 5 There is a report saying that allopurinol does not inhibit NSAID ulcer at a clinical dose to human (Non-Patent Reference 5).
  • Patent Reference 1 International Publication WO 92/09279 Patent Reference 2: JP-A 2002-105067 [Patent Reference 3: International Publication WO 96/31211 Patent Reference 4: JP-A 57-85379 Patent Reference 5: JP-A 6-211815 Patent Reference 6: JP-A 59-95272 Patent Reference 7: International Publication WO 98/18765 Patent Reference 8: JP-A 10-310578 Patent Reference 9: JP-A 6-65210 Non-Patent Reference 1: Biochemical Pharmacology, 2003, Vol. 65, pp. 683-695 Non-Patent Reference 2: Digestive Diseases and Sciences, 1998, Vol. 43, No. 9 (extra issue, 1998 Sept.), pp.
  • Non-Patent Reference 3 Journal of Pediatric Gastroenterology and Nutrition, 1995, Vol. 21, pp. 154-157
  • Non-Patent Reference 4 Journal of Surgical Research, 1994, Vol. 56, No. 1, pp. 45-52
  • Non-Patent Reference 5 Gut, 1996, Vol. 38, pp. 518-524
  • Non-Patent Reference 6 FEBS LETTERS, 1987, Vol. 213, No. 1, pp. 23-28
  • An object of the present invention is to provide an agent for treating or preventing digestive ulcer, which is effective also for ulcer in small intestine on which gastric secretion inhibitors such as proton pump inhibitors exert no effect, and which is superior to allopurinol in efficaciousness and safety.
  • Non-Patent References 1 to 3 describes that allopurinol is effective for a model with digestive ulcer but does not show the effectiveness for human (Non-Patent Reference 1), and animal models require a large amount of administration of 100 mg/kg.
  • the present invention also relates to an agent for use in a method of treating or preventing digestive ulcer, comprising a non-purine xanthine oxidase inhibitor as an active ingredient, wherein the inhibitor is a carboxylic acid derivative of the following formula (I) or a salt thereof:
  • the pharmaceutical composition of the present invention is useful as an agent for treating or preventing ulcer that formed in digestive tracts by the attack by gastric acid, pepsin, stress, Helicobacter pylori, NSAID, etc.
  • the pharmaceutical composition of the present invention is more advantageous to conventional ulcer-treating agents such as proton pump inhibitors, in that it is effective even for ulcer in small intestine, for which gastric/duodenal ulcer-treating agents that inhibit gastric acid secretion such as proton pump inhibitors are ineffective.
  • “Digestive ulcer” indicates an ulcer in which the partial defect of the epithelial tissue in the mucosal layer of a digestive tract has reached the depth. In particular, it means an ulcer formed in a digestive tract by the attack of gastric acid, pepsin, stress, Helicobacter pylori , NSAID, etc. "Digestive ulcer” quite differs from an ulcer formed in a digestive tract in autoimmune diseases such as inflammatory bowel disease. "Upper digestive ulcer” means the above-mentioned digestive ulcer that formed in esophagus, stomach and duodenum; and “lower digestive ulcer” means the above-mentioned digestive ulcer that formed in small intestine and large intestine.
  • the agent for treating or preventing digestive ulcer of the present invention is an agent for treating or preventing the above-mentioned "digestive ulcer", and especially preferably, it is an agent for treating digestive ulcer in small intestine for which the treating effect of conventional gastric secretion inhibitors cannot be expected.
  • "Non-purine” means that the compound has no purine skeleton in the molecule.
  • the purine skeleton means a ring skeleton of a bicyclic unsaturated hydrocarbon ring formed through condensation of a 5-membered ring and a 6-membered ring, which contains four nitrogen atoms.
  • the purine skeleton includes "purine”, which is the basic structure of purine nucleoside, or that is, “a ring skeleton formed through condensation of a pyridine ring and an imidazole ring”, and in addition, analogues that differ in the position of the nitrogen atom, for example, pyrazolopyrimidine, etc.
  • non-purine xanthine oxidase inhibitor is a xanthine oxidase inhibitor not having the above-mentioned purine skeleton in the molecule, and means other xanthine oxidase inhibitors than purine skeleton-having xanthine oxidase inhibitors (purine-type xanthine oxidase inhibitors) such as allopurinol or oxypurinol.
  • the non-purine xanthine oxidase inhibitor does not have a purine-like structure, and therefore differs from the purine-type xanthine oxidase inhibitor in the manner of the enzyme inhibition and, in addition, has a common characteristic in that the structure-derived side effect is weak.
  • the non-purine xanthine oxidase inhibitor is a compound of the above formula (I).
  • the NSAID includes salicylic acid compounds (aspirin, salicylic acid), anthranilic acid compounds (mefenamic acid), phenylacetic acid compounds (dichlofenac, fenbufen), indole-acetic acid compounds (indomethacin, sulindac), isoxazole-acetic acid compounds (mofezolac), pyrano-acetic acid compounds (etodolac), naphthalene compounds (nabumetone), propionylacetic acid compounds (ibuprofen, ketopurofen, loxoprofen, naproxen, zaltoprofen), oxicam compounds (piroxicam, meloxicam, lornoxicam), and basic antiinflammatory drugs (tiaramide hydrochloride, emorfazone
  • NSAIDs described in Konnichinochiryoyaku, 2005, pp. 86-115 (Nanko-do ); Drugs 49(1): 51-70, 1995 ; and Drugs 52 (Suppl. 5): 13-23, 1996 .
  • NSAID is not limited to these, and can include any others that may induce ulceration by their administration.
  • C 1-6 alkyl is, preferably linear alkyl such as methyl, ethyl, n-propyl, n-butyl, and branched alkyl such as isopropyl, isobutyl, tert-butyl, neopentyl. More preferred is C 1-4 alkyl; and even more preferred are methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • C 1-6 is alkylene, preferably linear alkylene such as methylene, ethylene, trimethylene, tetramethylene, and branched alkylene such as propylene, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene.
  • C 1-4 alkylene More preferred is C 1-4 alkylene.
  • the linear or branched alkyl having from 1 to 8 carbon atoms as A is preferably ethyl, n-propyl, isopropyl, n-butyl, isobutyl, isopentyl, neopentyl.
  • Alkenyl is a group having at least one double bond at any position of "alkyl", preferably C 2-8 alkenyl, more preferably C 2-8 alkenyl having at most 3 branches, even more preferably C 3-6 alkenyl having one double bond.
  • C 2-6 alkylene is a group having at least one double bond at any position, preferably propenylene, butenylene, pentenylene, hexenylene, 1,3-butadienylene, more preferably C 3-4 alkenylene.
  • the linear or branched alkenyl having from 2 to 8 carbon atoms for A is preferably propenyl, butenyl, butenyl, pentenyl, hexenyl, 1,3-butadienyl, isoprenyl, 3,3-dimethylpropen-2-yl.
  • "Halogen” indicates F, Cl, Br and I. Preferably, it is F and Cl.
  • Halogeno-C 1 -C 6 alkyl means C 1-6 alkyl substituted with at least one halogen, and is preferably C 1-6 alkyl substituted with at least one F, more preferably trifluoromethyl.
  • Cycloalkyl is a C 3-10 saturated hydrocarbon ring group, and may be bridged. Preferred is C 3-8 cycloalkyl; more preferred are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl; and even more preferred are cyclopentyl, cyclohexyl and cycloheptyl.
  • Aryl is a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and is preferably phenyl and naphthyl, more preferably phenyl.
  • "Optionally condensed aryl” is a generic term for the above-mentioned “aryl” and, in addition, for phenyl condensed with a 5- to 7-membered saturated monocyclic hetero ring containing 1 or 2 O atoms, and phenyl condensed with a C 3-8 saturated hydrocarbon ring.
  • Optionally-condensed aryl is preferably phenyl condensed with at least one ring selected from tetrahydrofuran, 1,3-dioxolane, 1,4-dioxepine, cyclohexane and cyclopentane, or non-condensed phenyl, and is more preferably non-condensed phenyl.
  • Heteroaryl is a generic term for a 5- or 6-membered monocyclic aromatic ring group having from 1 to 3 hetero atoms selected from O, S and N (monocyclic heteroaryl), and bicyclic or tricyclic heteroaryl constructed through condensation of the monocyclic heteroaryl rings or condensation of benzene ring and monocyclic heteroaryl ring.
  • the monocyclic heteroaryl is preferably pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl and isoxazolyl, more preferably thienyl, furyl, pyridyl, pyrrol-3-yl and pyrazol-4-yl.
  • the bicyclic hetero aryl is preferably benzothienyl, benzofuryl, indazolyl, benzothiazolyl, benzoxazolyl, indolyl, benzimidazolyl, quinazolyl, quinoxalinyl, quinolyl, isoquinolyl, cinnolinyl and phthalazinyl, more preferably benzothienyl, benzofuryl, indazolyl and indolyl.
  • the tricyclic heteroaryl is preferably carbazolyl, dibenzo[b,d]furanyl and dibenzo[b,d]thienyl.
  • the ring atom S may be oxidized to form an oxide or dioxide, or N may be oxidized to form an oxide.
  • the monocyclic heteroaryl of the ring B is preferably pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl and isoxazolyl, more preferably pyridyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl and isoxazolyl.
  • the above-mentioned "monocyclic heteroaryl of the ring B" is described as a nomenclature of a monovalent group for the convenience' sake, but the cyclic group is a divalent group that bonds to benzene ring and carboxyl group.
  • "Oxygen-containing saturated heterocyclic group” is a 5- to 7-membered saturated monocyclic heterocyclic group containing one or two O atoms, and is preferably oxiranyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.
  • Neitrogen-containing saturated heterocyclic group is a 5- to 8-membered saturated or partially-unsaturated monocyclic heterocyclic group containing one N atom and optionally further containing one hetero atom of N, S and O (monocyclic nitrogen-containing saturated heterocyclic group), or a cyclic group constructed through condensation of the monocyclic nitrogen-containing saturated heterocyclic group with benzene ring.
  • the ring atom S may be oxidized to form an oxide or dioxide, or N may be oxidized to form an oxide.
  • a carbon atom may be substituted with an oxo group.
  • the monocyclic nitrogen-containing saturated heterocyclic group is preferably pyrrolidinyl, piperidinyl, azepanyl, azocanyl or morpholinyl.
  • Preferred groups of G2 are halogen, -CN, lower alkyl, halogeno-lower alkyl, -O-R 5 , -O-halogeno-lower alkyl, -S-R 5 , -NR 3 R 4 , -CO 2 -R 5 and -lower alkylene-O-R 5 .
  • the substituents for R a to R c are preferably H and methyl.
  • X is preferably a bond or -O-.
  • A is preferably lower alkyl, monocyclic nitrogen-containing saturated heterocyclic group and phenyl.
  • R 2 is preferably -CN and -NO 2 , more preferably -CN.
  • R 7 is preferably H.
  • the compounds as the active ingredient of the pharmaceutical composition of the present invention may include tautomers and optical isomers depending on the type of the substituent therein; and the present invention includes mixtures of those isomers or isolated isomers.
  • the compounds as the active ingredient of the pharmaceutical composition of the present invention include "pharmaceutically-acceptable prodrugs".
  • “Pharmaceutically-acceptable prodrugs” are compounds that are metabolized in living bodies to give compounds having a group of CO 2 H, NH 2 , OH or the like for the active ingredient of the pharmaceutical composition of the present invention.
  • the group of forming prodrugs includes those described in Prog. Med. 5:2157-2161 (1985 ); and those described in " Development of Medicines", Vol. 7, Molecular Design, pp. 163-198, Hirokawa Publishing, 1990 .
  • Salts of the compounds as the active ingredient of the pharmaceutical composition of the present invention are pharmaceutically-acceptable salts, concretely including acid-addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid.
  • a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid
  • organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid,
  • the compounds may form salts with a base, including, for example, salts with an inorganic base containing a metal such as sodium, potassium, magnesium, calcium, aluminium, lithium, or an organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and ammonium salts.
  • a base including, for example, salts with an inorganic base containing a metal such as sodium, potassium, magnesium, calcium, aluminium, lithium, or an organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and ammonium salts.
  • the compounds or their salts as the active ingredient of the pharmaceutical composition of the present invention include various hydrates, solvates and polymorphic crystal substances.
  • Typical production methods for the compounds as the active ingredient of the pharmaceutical composition of the present invention are described below.
  • those shown in the above-mentioned Patent References 1 to 9 may be produced with reference to the production methods described in those patent publications.
  • Benzotriazole derivatives ( WO 03/042185 ), triazole derivatives ( WO 03/064410 ) and tetrazole derivatives ( WO 2004/009563 ) may be produced with reference to the production methods described in the corresponding patent publications.
  • the compounds of formula (I) that are used as the active ingredient of the pharmaceutical composition of the present invention may be produced according to various known production methods, taking advantage of the characteristics based on the basic skeleton or the type of the substituent therein.
  • the functional group includes, for example, an amino group, a hydroxyl group and a carboxyl group
  • their protective groups are, for example, protective groups described in Protective Groups in Organic Synthesis (by T. W. Greene and P. G. M.
  • the method comprises introducing the protective group, then reacting the compound, and if desired, removing the protective group or converting it into a desired group, thereby obtaining a desired compound.
  • the prodrugs of the compounds of formula (I) or their salts may be produced by introducing a specific group into the starting compound or intermediate, like the above-mentioned protective group, or by directly processing the compounds of formula (I).
  • the reaction may be any ordinary esterification, amidation, acylation or the like known to those skilled in the art.
  • Q 1 represents -B(OH) 2 or -B(OR 11 )OR 12 ;
  • L 1 represents a leaving group.
  • R 11 and R 12 are the same or different, each representing lower alkyl, or R 11 and R 12 , taken together, form lower alkylene. The same shall apply hereinunder.
  • This production method is for producing the compounds (I) of the present invention through coupling reaction of the compound (1) and the compound (2).
  • the leaving group for L 1 includes halogen, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy.
  • the compounds (1) and (2) are used in the same amount or any one of them is used excessively, and they are reacted in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature or under heat with reflux generally for 0.1 hours to 5 days.
  • the reaction is attained in an inert gas atmosphere.
  • microwave radiation may be favorable for the heating in the reaction.
  • the solvent includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane; halogenohydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform; alcohols such as methanol, ethanol, 2-propanol, butanol; N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), water; and their mixed solvents.
  • aromatic hydrocarbons such as benzene, toluene, xylene
  • ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane
  • the base is preferably an inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide. Also usable are other bases such as potassium fluoride, cesium fluoride.
  • the reaction is preferably attained in an aprotic solvent.
  • the palladium catalyst is preferably tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium chloride-1,1'-bis(diphenylphosphino)ferrocene.
  • a 1 represents aryl or heteroaryl of the groups of A in formula (I); Q 2 is the same as Q 1 ; and L 2 is the same as L 1 . The same shall apply hereinunder.
  • This production method is a method for producing the compound (Ia) of the present invention where A is aryl or heteroaryl in formula (I), through coupling reaction of the compound (3) and the compound (4).
  • the reaction reagents and the reaction conditions for the first production method are applicable also to this production method.
  • X 1 represents -O-, -N(R 6 )- or -S-; L 3 represents a leaving group or OH. The same shall apply hereinunder.
  • This production method is a method for producing the compound (Ib) of the present invention where X 1 is -O-, -N(R 6 )- or -S- in formula (I), through alkylation of the compound of formula (5).
  • the leaving group for L 3 includes halogen, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy.
  • this production method is as follows:
  • the compound (5) and the alkylating agent (6) are used in the same amount of the alkylating agent (6) is used excessively, and they are reacted in a solvent inert to the reaction at room temperature or under heat with reflux generally for 0.1 hours to 5 days.
  • the solvent includes aromatic hydrocarbons, ethers, halogenohydrocarbons, DMF, NMP, DMSO, and their mixed solvents, such as those mentioned hereinabove.
  • the reaction is preferably attained in the presence of a base or a phase transfer catalyst.
  • the base includes organic bases such as triethylamine, diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU); and inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride.
  • the phase transfer catalyst includes tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, 18-crown-6.
  • the alkylation may be attained by using the compound (5) and the alkylating agent (6) in the same amount or by using the alkylating agent (6) excessively, and by processing them with an azodicarboxylic acid derivative such as ethyl azodicarboxylate or 1,1'-(azodicarbonyl)dipiperidine, and a phosphorus compound such as triphenyl phosphine or tributyl phosphine.
  • an azodicarboxylic acid derivative such as ethyl azodicarboxylate or 1,1'-(azodicarbonyl)dipiperidine
  • a phosphorus compound such as triphenyl phosphine or tributyl phosphine.
  • a 2 represents a nitrogen-containing heterocyclic group or heteroaryl containing at least one nitrogen atoms of the groups of A in formula (I), and this is a cyclic group bonding to the benzene ring via the nitrogen atom. The same shall apply hereinunder.
  • This production method is a method for producing the compound (Ic) of the present invention through ipso-substitution between the compound (7) and the compound (8).
  • the compounds of the present invention having various functional groups may also be produced according to methods obvious to those skilled in the art, or according to known production methods, or according to modifications of such methods.
  • the compounds of the present invention produced in the above-mentioned production methods may be further subjected to substituent modification reaction, thereby producing desired compounds of the present invention. Typical reactions are mentioned below.
  • those having an amide group or those having an ester group may be produced, starting from a compound having a hydroxyl group or an amino group and reacting it with a carboxylic acid or its reactive derivative.
  • a reaction for example, referred to are the methods described in " Courses in Experimental Chemistry", 4th Ed., Vol. 22 (1992), edited by the Chemical Society of Japan, Maruzen .
  • those having a sulfonyl group or a sulfenyl group may be produced through oxidation of a compound having a sulfide group.
  • a compound having a sulfide group For example, it may be attained according to the methods described in " Courses in Experimental Chemistry", 4th Ed., Vol. 23 (1991), edited by the Chemical Society of Japan, Maruzen .
  • those having a lower alkoxy group or a lower alkylamino group may be produced through alkylation of a compound having a hydroxyl group or an amino group.
  • the reaction may be attained under the same condition as in the third production method.
  • the compound (1a) where X is X 1 , the compound (1a) where X is a bond and A is A 2 , and the compound (1c) where X is a bond and A is A 1 may be produced according to the above-mentioned reaction routes.
  • the same condition as in the above-mentioned third production method is applicable to the alkylation.
  • the ipso-substitution may be attained under the same condition as that for the alkylation in the above-mentioned third production method where L 3 is a leaving group.
  • the same condition as that for the above-mentioned first production method is applicable.
  • the boration may be attained according to the methods described in " Chem. Rev., 95, 2547-2483,(1995 )", “ J. Org. Chem., 67, 5394-5397 (2002 )", “ J. Org. Chem., 65, 164-168 (2000 )” or " J. Org. Chem., 60, 7508-7510 (1995 )".
  • L 4 represents sulfonyloxy such as methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy.
  • the starting compound (4a) can be produced according to the above-mentioned reaction route.
  • the boration and the hydrolysis are the same as those in the above-mentioned production methods for starting compounds; and the coupling reaction may be attained under the same condition as in the above-mentioned first production method.
  • the sulfonylesterification may be attained in an ordinary manner.
  • the phenolic hydroxyl group and the carboxyl group of the compounds are preferably protected with a protective group.
  • the protective group and the condition for protection and deprotection referred to are the methods described in the above-mentioned " Protective Groups in Organic Synthesis", 3rd Ed., 1999 .
  • the compounds produced in the manner as above may be isolated and purified directly as they are free compounds or after salt formation in an ordinary manner as salts.
  • the isolation and purification may be attained in ordinary chemical operation of extraction, concentration, distillation, crystallization, filtration, recrystallization or various chromatography.
  • Various isomers may be isolated in an ordinary manner, utilizing the difference in physicochemical properties between the isomers.
  • optical isomers may be separated and purified according to a method comprising introducing a racemic compound into a diastereomer salt with an optically-active organic acid (tartaric acid, etc.) followed by fractionation and crystallization, or a method of column chromatography using a chiral filler.
  • Optically-active compounds may be produced, using suitable optically-active compounds as starting compounds.
  • a diastereomer mixture may also be isolated through fractionating crystallization or chromatography.
  • the pharmaceutical composition of the present invention containing a non-purine xanthine oxidase inhibitor as the active ingredient may be formulated, using a carrier, a vehicle and other additives that are generally usable in ordinary pharmaceutical preparations.
  • the administration may be attained in any route of oral administration with tablets, pills, capsules, granules, powders or liquids, or parenteral administration with intravenous or injections for intramuscular injections, or suppositories, percutaneous preparations, nasal preparations or inhalants.
  • the dose may be suitably determined for individuals, depending on the conditions, the age and the sex of the patients to which they are administered, but is, in general, from 0.001 to 100 mg/kg adult/day, more preferably from 0.01 to 30 mg/kg adult/day for oral administration, and this is administered all at a time or, as divided in portions, administered 2 to 4 times a day.
  • the dose may be from 0.0001 to 10 mg/kg adult/day, more preferably from 0.001 to 1 mg/kg adult/day, and this is administered all at a time or, as divided in portions, administered plural times a day.
  • the dose may be from 0.0001 to 1 mg/kg adult/day, and this is administered all at a time or, as divided in portions, administered plural times a day.
  • the content of the active ingredient in the preparation may be from 0.0001 to 80 %, more preferably from 0.001 to 50 %.
  • the solid composition for oral administration of the present invention employed are tablets, powders, granules, etc.
  • the solid composition of those types comprises one or more active substances along with at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, magnesium meta-silicate aluminate.
  • the composition may contain any other additives, for example, a lubricant such as magnesium stearate, a disintegrator such as sodium carboxymethyl starch, and a dissolution promoter.
  • a lubricant such as magnesium stearate
  • a disintegrator such as sodium carboxymethyl starch
  • a dissolution promoter e.g., sodium carboxymethyl starch
  • the tablets and pills may be coated wit sugar or with a gastric or enteric coating agent.
  • the liquid composition for oral administration includes pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, which contain ordinary inert solvents such as purified water or ethanol. In addition to the inert solvents, those compositions may further contain pharmaceutical aids such as solubilizers, wetting promoters, suspension promoters, and also sweeteners, flavorings, aromas, and preservatives.
  • the injection for parenteral administration includes germ-free, water-base or water-free solutions, suspensions and emulsions.
  • the water-base solvents include, for example, distilled water for injection and physiological saline water.
  • the water-free solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, Polysolvate 80 (Japan Pharmacopeia name), etc.
  • Those compositions may further contain additives such as isotonicating promoters, preservatives, wetting promoters, emulsifiers, dispersants, stabilizers, dissolution promoters. These are sterilized by filtering them through bacteria-trapping filters, or by adding microbicides thereto, or by exposing them to radiations.
  • the germ-free, solid compositions thus produced may be dissolved or suspended in germ-free water or in germ-free solvents for injection, before using them.
  • Transmucosal preparations such as inhalants or nasal preparations may be solid, liquid or semisolid, and may be produced in any conventional known methods.
  • a vehicle such as lactose or starch, and further a pH-controlling agent, a preservative, a surfactant, a lubricant, a stabilizer and a tackifier may be suitably added thereto.
  • a suitable device for inhalation of insufflation For example, using a known device or spray such as device for metering administration inhalation, the compound may be administered, as a powder of itself alone or a formulated mixture, or as a solution or suspension combined with a pharmaceutically-acceptable carrier.
  • the dry powder inhalator may be for single use or repeated multiple use, for which usable are dry powder or powder-containing capsules. Further, it may also be a pressure aerosol spray or the like that uses a suitable propellant, for example, a suitable vapor such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
  • a suitable propellant for example, a suitable vapor such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
  • a low-melting point wax for example, a fatty acid glyceride mixture or cocoa butter is melted, an active ingredient is added thereto, and uniformly dispersed by stirring. Next, this is injected into a suitable mold, cooled and solidified therein.
  • the liquid preparation includes solution, suspension, retention enemas and emulsion, as well as water or aqueous propylene glycol solution.
  • the pharmaceutical composition of the present invention is a combination or a mixture of an agent for treating or preventing digestive ulcer and a non-steroidal antiinflammatory drug
  • the amount of each ingredient may be suitably determined as the clinical effective amount thereof in its administration as a single preparation depending on the condition of each patient.
  • the agent for treating or preventing digestive ulcer of the present invention may be suitably combined with any other therapeutically-effective gastric secretion inhibitor, for example, a proton pump inhibitor or an H 2 blocker.
  • any other therapeutically-effective gastric secretion inhibitor for example, a proton pump inhibitor or an H 2 blocker.
  • the two may form a combined preparation for simultaneous administration, or may form different preparations for separate administration.
  • a substituted phenyl group is represented as "numeral indicating the substituent position-abbreviation of the substituent-Ph" in the Tables. "di" before the substituent means that the group has two substituents.
  • 4-MeO-3,5-diMe-Ph- means 4-methoxy-3,5-dimethylphenyl group.
  • Methyl 3-fluoroisonicotinate was oxidized with 3-chloroperbenzoic acid, followed by heating in the presence of phosphoryl chloride. The product was separated by silica gel column chromatography to obtain methyl 2-chloro-5-fluoroisonicotinate (EI: 189) and methyl 2-chloro-3-fluoroisonicotinate (EI: 189).
  • Methyl 2-(3-cyano-4-benzyloxy-5-fluorophenyl)isonicotinate is stirred at room temperature in methanol-THF (1:1) under a hydrogen atmosphere at normal pressure in the presence of palladium-carbon to obtain methyl 2-(3-cyano-5-fluoro-4-hydroxyphenyl)isonicotinate.
  • FN 271.
  • Ethyl 2-[4-(benzyloxy)-3-cyanophenyl]-4-methyl-1,3-thiazole-5-carboxylate was suspended in a mixture of THF and ethanol, then palladium-carbon was added thereto, and the mixture was stirred under a hydrogen atmosphere at room temperature to obtain ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate.
  • APN 287.
  • Methyl 2-(3-cyano-4-hydroxyphenyl)isonicotinate and trifluoromethanesulfonic anhydride were reacted at 0°C in dichloromethane in the presence of diisopropylethylamine to obtain methyl 2-(3-cyano-4- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ phenyl)isonicotinate.
  • 5-Bromo-2-iodobenzonitrile and 3-pyridylboric acid were dissolved in a mixture solution of aqueous 2 M sodium carbonate solution and toluene, then tetrakis(triphenylphosphine)palladium was added thereto, and the mixture was heated, stirred with heating in an argon atmosphere at 100°C for 3 days to obtain 5-bromo-2-pyridin-3-ylbenzonitrile.
  • EI 258, 260.
  • Methyl 5-(4-hydroxyphenyl)thiophene-2-carboxylate was obtained in accordance with the method of Reference Preparation Example 6 using methyl 5-(4-benzyloxyphenyl)thiophene-2-carboxylate and pentamethylbenzene.
  • reaction liquid was evaporated under reduced pressure, and then purified in the same manner as that for the purification treatment in Example 13 to obtain 9.2 mg of 5-(4'-amino-2-cyano-3'-fluorobiphenyl-4-yl)thiophene-2-carboxylic acid.
  • the compounds of formula (I) that are the active ingredient of the pharmaceutical composition of the present invention may be formed into pharmaceutical compositions according to the following formulation.
  • 100 g of an active ingredient is taken and mixed with 652 g of lactose and 163 g of corn starch.
  • the mixture is, as combined with 300 g of an aqueous solution of 10 % hydroxypropyl cellulose (for example, Nippon Soda's HPC-SL), granulated and dried using a fluidized layer granulator.
  • the dried product is mixed with 50 g of low-substitution hydroxypropyl cellulose (for example, Shinetsu Chemical's L-HPC), and further mixed with 5 g of magnesium stearate to prepare a mixture powder for tabletting.
  • a rotary tabletting machine for example, by Kikusui
  • the mixture powder is tabletted into tablets of 200 mg each.
  • test compound was dissolved in DMSO (by Nacalai) to have a concentration of 10 mM, and then just before use, its concentration was adjusted to a desired one.
  • the xanthine oxidase inhibitory activity of the compound of the present invention was evaluated according to a partly modified method of a method described in a reference " Free Radic. Biol. Med. 6, 607-615, 1992 ". Concretely, xanthine oxidase (derived from butter milk, by Sigma) was mixed with 50 mM phosphate buffer to be 0.03 units/ml, and applied to a 96-well plate in an amount of 50 ⁇ l/well. The test compound diluted to have a final concentration was added to the plate in an amount of 2 ⁇ l/well, and processed at room temperature for 20 minutes.
  • Pterin (by Sigma) was added to it to have a final concentration of 5 ⁇ M in an amount of 50 ⁇ l/well, and reacted at room temperature for 10 minutes. Under a condition of excitation at 345 nm and emission at 390 nm (pterin is oxidized by xanthine oxidase to give isoxanthopterin, and under the condition it emits light), the sample was analyzed using a microplate reader sapphire (by Tacan).
  • the light emission by isoxanthopterin in the presence or absence of xanthine oxidase was defined as 0% inhibition and 100% inhibition, respectively, and the concentration (IC 50 ) of the test compound for 50% inhibition was computed.
  • the compounds of formula (I) had good xanthine oxidase inhibiting activity.
  • IC 50 of typical compounds in Preparation Examples are shown in the following Table 21.
  • Patent Reference 1 says that IC 50 for xanthine oxidase inhibiting activity of the compound A (Example 77 in Patent Reference 1) referred to in the following Example is 1.8 nM.
  • a reference says that IC 50 for xanthine oxidase inhibiting activity of the compound B (Example 12 in Patent Reference 7) is 5.8 nM ( Bioorganic Medicinal Chemistry Letters, 11, 2001, 879-882 , Compound No. 5e).
  • Compound A 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid.
  • Compound B 1-(3-cyano-4-neopentyloxyphenyl)-1H-pyrazole-4-carboxylic acid.
  • the test compound was controlled to be 10 mg/kg or 30 mg/kg.
  • a control group was separately prepared, in which 5 ml/kg of the 0.5 % MC solution was orally administered to the rats. After 1 hour, 40 mg/kg of NSAID, diclofenac (by Sigma) was orally administered to all rats of all groups, as a suspension in 0.5 % MC solution (5 ml/kg).
  • the antiulceration potency (%) of the test compound was computed according to the following formula: Antiulceration Potency % : 1 - mean ulcer length of compound - administered group / mean ulcer length of 0.5 % MC - administered group ⁇ 100.
  • the compounds as the active ingredient of the pharmaceutical composition of the present invention showed a significant (Student's t-test, p ⁇ 0.05) inhibitory potency, as compared with the control group.
  • the inhibitory potency of each compound is shown in the parenthesis after the Preparation Example Number.
  • Preparation Example 8 (72%: 30 mg/kg), 183 (27%: 30 mg/kg), 237 (32%: 10 mg/kg), 251 (43%: 30 mg/kg), 254 (32%: 30 mg/kg), Compound A (36%: 30 mg/kg), Compound B (43%: 30 mg/kg).
  • the test compound was controlled to be 10 mg/kg in every case.
  • a control group was separately prepared, in which 5 ml/kg of the 0.5 % MC solution was orally administered to the rats. After 1 hour, 10 mg/kg of NSAID, indomethacin (by Sigma) was orally administered to the rats, as a suspension in 0.5 % MC solution (5 ml/kg).
  • the test compound was again orally administered to every rat in the same amount as previously; and after 24 hours, the area of the ulcer formed in the small intestine was measured using a stereomicroscope (by Nikon) and a micrometer (by Olympus), and the data of 10 cases were averaged.
  • the antiulceration potency (%) of the test compound was computed according to the following formula: Antiulceration Potency % : 1 - mean ulcer area of compound - administered group / mean ulcer area of 0.5 % MC - administered group ⁇ 100.
  • the compounds of the present invention showed a remedial effect both in the gastric ulcer model and the small intestine ulcer model, and no conventional remedies could have the effect.
  • test results shown in the above-mentioned Examples confirm that the compounds as the active ingredient of the pharmaceutical composition of the present invention have a strong potency of xanthine oxidase inhibition, and in animal tests, the compounds show an excellent effect of curing digestive ulcer. Accordingly, these compounds are expected as an agent for treating or preventing ulcer that forms in digestive tracts by the attack thereto such as gastric acid, pepsin, stress, Helicobacter pylori bacteria or NSAID. Further, the compounds as the active ingredient of the pharmaceutical composition of the present invention do not have a purine structure and their toxicity is low, and accordingly, they are superior to allopurinol in the efficaciousness as so mentioned in the above.
  • the pharmaceutical composition of the present invention is useful as an agent for treating or preventing ulcer that forms in digestive tracts by the attack of gastric acid, pepsin, stress, Helicobacter pylori, NSAID, etc.
  • the pharmaceutical composition of the present invention is effective also for ulcer in small intestine, for which remedies for gastric/duodenal ulcer that inhibit gastric acid secretion such as proton pump inhibitors are ineffective, and is therefore useful as an ulcer-treating agent heretofore unknown in the art.
  • it is superior to allopurinol in the efficaciousness and the safety.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP07714807A 2006-02-24 2007-02-22 Remedy or preventive for digestive ulcer Not-in-force EP1992361B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PL07714807T PL1992361T3 (pl) 2006-02-24 2007-02-22 Środek do leczenia lub zapobiegania wrzodowi trawiennemu

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006048914 2006-02-24
PCT/JP2007/053310 WO2007097403A1 (ja) 2006-02-24 2007-02-22 消化管潰瘍治療又は予防薬

Publications (3)

Publication Number Publication Date
EP1992361A1 EP1992361A1 (en) 2008-11-19
EP1992361A4 EP1992361A4 (en) 2010-07-28
EP1992361B1 true EP1992361B1 (en) 2012-05-02

Family

ID=38437439

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07714807A Not-in-force EP1992361B1 (en) 2006-02-24 2007-02-22 Remedy or preventive for digestive ulcer

Country Status (12)

Country Link
US (2) US8067446B2 (ja)
EP (1) EP1992361B1 (ja)
JP (1) JP5115474B2 (ja)
KR (1) KR20080097456A (ja)
CN (1) CN101389352B (ja)
AT (1) ATE555810T1 (ja)
CA (1) CA2643272A1 (ja)
ES (1) ES2383766T3 (ja)
MX (1) MX2008010646A (ja)
PL (1) PL1992361T3 (ja)
PT (1) PT1992361E (ja)
WO (1) WO2007097403A1 (ja)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2014235063B2 (en) * 2013-03-15 2017-05-04 Purdue Pharma L.P. Carboxamide derivatives and use thereof

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5563985B2 (ja) * 2008-10-15 2014-07-30 キッセイ薬品工業株式会社 フェニルイソニコチン酸誘導体及びその医薬用途
WO2010044410A1 (ja) * 2008-10-15 2010-04-22 キッセイ薬品工業株式会社 ビアリールイソニコチン酸誘導体及びその医薬用途
JP2012096999A (ja) * 2009-02-27 2012-05-24 Nagoya Univ ニッケル触媒を用いたカップリング法によるフェニル置換複素環誘導体の製造法
ES2459722T3 (es) * 2009-02-27 2014-05-12 Teijin Pharma Limited Procedimiento para producir un derivado heterocíclico sustituido con fenilo mediante acoplamiento usando un catalizador de metal de transición
CN101580495A (zh) * 2009-05-25 2009-11-18 沈阳药科大学 5-取代苯基-3-异噁唑甲酸及其酯类化合物、组合物及其制备方法
WO2011073617A1 (en) * 2009-12-14 2011-06-23 Cipla Limited Processes for the preparation of febuxostat and salts thereof
ES2589977T3 (es) 2010-08-27 2016-11-17 Teijin Pharma Limited Método para la producción de derivados heterocíclicos sustituidos con fenilos mediante medios de método de acoplamiento utilizando un compuesto de palladio
US8946432B2 (en) 2011-07-05 2015-02-03 Lupin Limited Biaryl derivatives as nAChR modulators
CN102875566B (zh) * 2011-07-15 2014-08-13 天津药物研究院 具有抗胃溃疡作用的噻吩衍生物
HUE034802T2 (en) * 2011-08-30 2018-02-28 Chdi Foundation Inc Kinurenin-3-monooxygenase inhibitors, pharmaceutical preparations and methods of use
US20140228417A1 (en) * 2011-10-05 2014-08-14 Mapi Pharma Ltd. Process and intermediates for the preparation of substituted 2-arylthiazole carboxylic acids
NO2980085T3 (ja) 2013-03-29 2018-08-11
WO2014192977A1 (ja) * 2013-05-31 2014-12-04 帝人ファーマ株式会社 チアゾール誘導体
KR20170026633A (ko) 2014-07-17 2017-03-08 씨에이치디아이 파운데이션, 인코포레이티드 Hiv-관련 장애의 치료 방법 및 치료용 조성물
CN108929275B (zh) * 2018-06-14 2021-08-24 沈阳药科大学 6-(3,4-取代苯基)-3-氧代-2,3-二氢哒嗪-4-酰肼类化合物及其用途
CN108484494B (zh) * 2018-06-15 2021-07-30 沈阳药科大学 2-氧代-1,2-二氢吡啶-4-甲酸类化合物
CN110204493B (zh) * 2019-07-01 2021-05-14 华南理工大学 三环类xor抑制剂及其制备方法和应用
CN112979559A (zh) * 2021-03-08 2021-06-18 沈阳药科大学 2-苯基嘧啶甲酸衍生物及其制备方法和应用
CN113004208A (zh) * 2021-03-08 2021-06-22 沈阳药科大学 一种抑制黄嘌呤氧化酶活性的化合物及制备方法和应用
CN112957360B (zh) * 2021-03-09 2022-06-03 中国医科大学附属第一医院 一种靶向hmmr磷酸化的小分子抑制剂及其应用

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4346094A (en) 1980-09-22 1982-08-24 Eli Lilly And Company 3-Aryl-5-isothiazolecarboxylic acids and related compounds used to lower uric acid levels
US4495195A (en) 1982-11-01 1985-01-22 Eli Lilly And Company Xanthine oxidase inhibiting 3(5)-phenyl-substituted-5(3)-pyrazole-carboxylic acid derivatives, compositions, and methods of use
CA2073981C (en) * 1990-11-30 2002-01-08 Shiro Kondo 2-arylthiazole derivatives and pharmaceutical composition thereof
JP3399559B2 (ja) 1992-08-12 2003-04-21 帝人株式会社 ２−フェニル複素環式化合物
JP3113110B2 (ja) 1993-01-19 2000-11-27 帝人株式会社 イソキサゾールおよびイソチアゾール誘導体
ES2224160T3 (es) 1995-04-07 2005-03-01 Teijin Limited Agente protector para organo o tejido.
ID21775A (id) 1996-10-25 1999-07-22 Yoshitomi Pharmaceutical Senyawa-senyawa 1-fenilpirazol dan penggunaan farmasinya
JPH10310578A (ja) 1996-11-13 1998-11-24 Yoshitomi Pharmaceut Ind Ltd ３−フェニルピラゾール化合物
JP2002105067A (ja) 2000-09-28 2002-04-10 Teijin Ltd ２−フェニルチアゾール誘導体、およびそれを有効成分とする医薬組成物
WO2006022375A1 (ja) * 2004-08-27 2006-03-02 Astellas Pharma Inc. ２－フェニルチオフェン誘導体
KR20070045272A (ko) * 2004-08-27 2007-05-02 아스텔라스세이야쿠 가부시키가이샤 2-페닐피리딘 유도체

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2014235063B2 (en) * 2013-03-15 2017-05-04 Purdue Pharma L.P. Carboxamide derivatives and use thereof
US10005768B2 (en) 2013-03-15 2018-06-26 Purdue Pharma L.P. Carboxamide derivatives and use thereof

Also Published As

Publication number Publication date
CN101389352A (zh) 2009-03-18
MX2008010646A (es) 2008-10-14
US8426453B2 (en) 2013-04-23
JPWO2007097403A1 (ja) 2009-07-16
US20090036428A1 (en) 2009-02-05
JP5115474B2 (ja) 2013-01-09
CA2643272A1 (en) 2007-08-30
CN101389352B (zh) 2012-09-19
WO2007097403A1 (ja) 2007-08-30
EP1992361A4 (en) 2010-07-28
US8067446B2 (en) 2011-11-29
KR20080097456A (ko) 2008-11-05
PT1992361E (pt) 2012-07-10
EP1992361A1 (en) 2008-11-19
ATE555810T1 (de) 2012-05-15
PL1992361T3 (pl) 2012-10-31
ES2383766T3 (es) 2012-06-26
US20110281919A1 (en) 2011-11-17

Similar Documents

Publication Publication Date Title
EP1992361B1 (en) Remedy or preventive for digestive ulcer
JP5040656B2 (ja) トリアリールカルボン酸誘導体
JP5068768B2 (ja) １１ベータ−ｈｓｄ１阻害剤としてのチアゾール
JP4894517B2 (ja) ２−フェニルピリジン誘導体
US8524756B2 (en) Compounds for inflammation and immune-related uses
US7612108B2 (en) 2-phenylthiophene derivative
PT1852433E (pt) Derivados de carbazole, seus solvatos ou seus sais farmaceuticamente aceitáveis
JPWO2002072145A1 (ja) Ｅｐ１アンタゴニストを有効成分として含有するうつ病の治療剤
JP2010513403A (ja) Ｓｃｄ阻害剤としての２−置換５員ヘテロ環
TWI317359B (en) N-phenyl-arylsulfonamide compound and the pharmaceuticals containing the same as active ingredient
CN105017242B (zh) 新型联苯杂环类衍生物、其制备方法及其作为药物的用途

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20080821

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

A4 Supplementary search report drawn up and despatched

Effective date: 20100628

17Q First examination report despatched

Effective date: 20110302

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RTI1 Title (correction)

Free format text: REMEDY OR PREVENTIVE FOR DIGESTIVE ULCER

DAX Request for extension of the european patent (deleted)
GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 555810

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120515

Ref country code: CH

Ref legal event code: EP

Ref country code: CH

Ref legal event code: NV

Representative=s name: BOVARD AG

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2383766

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20120626

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602007022420

Country of ref document: DE

Effective date: 20120628

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20120704

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20120401212

Country of ref document: GR

Effective date: 20120614

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

Effective date: 20120502

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120502

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120902

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120502

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120502

REG Reference to a national code

Ref country code: PL

Ref legal event code: T3

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120502

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120502

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120502

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120502

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120502

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120502

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120502

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PT

Payment date: 20121226

Year of fee payment: 7

Ref country code: GR

Payment date: 20121227

Year of fee payment: 7

Ref country code: ES

Payment date: 20121227

Year of fee payment: 7

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20130205

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20130104

Year of fee payment: 7

Ref country code: DE

Payment date: 20130220

Year of fee payment: 7

Ref country code: FR

Payment date: 20130123

Year of fee payment: 7

Ref country code: IE

Payment date: 20130208

Year of fee payment: 7

Ref country code: SE

Payment date: 20130222

Year of fee payment: 7

Ref country code: CH

Payment date: 20130207

Year of fee payment: 7

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602007022420

Country of ref document: DE

Effective date: 20130205

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PL

Payment date: 20130104

Year of fee payment: 7

Ref country code: BE

Payment date: 20130131

Year of fee payment: 7

Ref country code: NL

Payment date: 20130227

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20130227

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120802

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130228

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20140822

BERE Be: lapsed

Owner name: ASTELLAS PHARMA INC.

Effective date: 20140228

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602007022420

Country of ref document: DE

REG Reference to a national code

Ref country code: NL

Ref legal event code: V1

Effective date: 20140901

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 555810

Country of ref document: AT

Kind code of ref document: T

Effective date: 20140222

REG Reference to a national code

Ref country code: GR

Ref legal event code: ML

Ref document number: 20120401212

Country of ref document: GR

Effective date: 20140903

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20140222

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140228

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140903

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140228

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140901

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20141031

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602007022420

Country of ref document: DE

Effective date: 20140902

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140223

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140222

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140822

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140228

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140228

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140222

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140902

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140222

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140222

REG Reference to a national code

Ref country code: PL

Ref legal event code: LAPE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20070222

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130222

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140222

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140223

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140222